Acute lung injury (ALI) is the leading cause of death in intensive care units. Extracellular histones have recently been recognized to be pivotal inflammatory mediators. Heparin and its derivatives can bind histones through electrostatic interaction. The purpose of this study was to investigate 1) the role of extracellular histones in the pathogenesis of ALI caused by acid aspiration and 2) whether N-acetyl-heparin (NAH) provides more protection than heparin against histones at the high dose. ALI was induced in mice via intratracheal instillation of hydrochloric acid (HCl). Lethality rate, blood gas, myeloperoxidase (MPO) activity, lung edema and pathological changes were used to evaluate the degree of ALI. Heparin/NAH was administered intraperitoneally, twice a day, for 3 days or until death. Acid aspiration caused an obvious increase in extracellular histones. A significant correlation existed between the concentration of HCl aspirated and the circulating histones. Heparin/NAH (10 mg/kg) improved the lethality rate, blood gas, MPO activity, lung edema and pathological score. At a dose of 20 mg/kg, NAH still provided protection, however heparin tended to aggravate the injury due to hemorrhagic complications. The specific interaction between heparin and histones was verified by the binding assay. In summary, high levels of extracellular histones can be pathogenic in ALI caused by acid aspiration. By neutralizing extracellular histones, heparin/NAH can offer similar protection at the moderate doses. At the high dose, NAH provides better protection than heparin.
References
[1]
Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. (2012) Acute respiratory distress syndrome: the Berlin Definition. JAMA 307(23): 2526–2533.
[2]
Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. New Engl J Med 342(18): 1334–1349. doi: 10.1056/nejm200005043421806
[3]
Tsukamoto T, Chanthaphavong RS, Pape HC (2010) Current theories on the pathophysiology of multiple organ failure after trauma. Injury 41(1): 21–26. doi: 10.1016/j.injury.2009.07.010
[4]
Ciesla DJ, Moore EE, Johnson JL, Burch JM, Cothren CC, et al. (2005) The role of the lung in postinjury multiple organ failure. Surgery 138(4): 749–757. doi: 10.1016/j.surg.2005.07.020
[5]
Raghavendran K, Nemzek J, Napolitano LM, Knight PR (2011) Aspiration-induced lung injury. Crit Care Med 39(4): 818–826. doi: 10.1097/ccm.0b013e31820a856b
[6]
Abdulla S (2013) Pulmonary aspiration in perioperative medicine. Acta Anaesthesiol Belg 64(1): 1–13.
[7]
Olsson GL, Hallen B, Hambraeus-Jonzon K (1986) Aspiration during anaesthesia: A computer aided study of 185,358 anaesthetics. Acta Anaesthesiol Scand 30(1): 84–92. doi: 10.1111/j.1399-6576.1986.tb02373.x
[8]
Matthay MA, Zemans RL (2011) The acute respiratory distress syndrome: pathogenesis and treatment. Annu Rev Pathol 6: 147–163. doi: 10.1146/annurev-pathol-011110-130158
[9]
Matthay MA, Zimmerman GA (2005) Acute lung injury and the acute respiratory distress syndrome: Four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 33(4): 319–327. doi: 10.1165/rcmb.f305
[10]
Zhang H, Villar J, Slutsky AS (2013) Circulating histones: a novel target in acute respiratory distress syndrome? Am J Respir Crit Care Med 187(2): 118–120. doi: 10.1164/rccm.201211-2025ed
[11]
Xu J, Zhang X, Monestier M, Esmon NL, Esmon CT (2011) Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol 187(5): 2626–2631. doi: 10.4049/jimmunol.1003930
[12]
Huang H, Evankovich J, Yan W, Nace G, Zhang L, et al. (2011) Endogenous histones function as alarmins in sterile inflammatory liver injury through Toll-like receptor 9 in mice. Hepatology 54(3): 999–1008. doi: 10.1002/hep.24501
[13]
Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, et al. (2009) Extracellular histones are major mediators of death in sepsis. Nat Med 15(11): 1318–1321. doi: 10.1038/nm.2053
[14]
Abrams ST, Zhang N, Manson J, Liu T, Dart C, et al. (2013) Circulating histones are mediators of trauma associated lung injury. Am J Respir Crit Care Med 187(2): 160–169. doi: 10.1164/rccm.201206-1037oc
[15]
Ludwig RJ (2009) Therapeutic use of heparin beyond anticoagulation. Curr Drug Discov Technol 6(4): 281–289. doi: 10.2174/157016309789869001
[16]
Nakamura T, Vollmar B, Winning J, Ueda M, Menger MD, et al. (2001) Heparin and the nonanticoagulant N-acetyl heparin attenuate capillary no-reflow after normothermic ischemia of the lung. Ann Thorac Surg 72(4): 1183–1188. doi: 10.1016/s0003-4975(01)02959-9
[17]
Alcantara FF, Iglehart DJ, Ochs RL (1999) Heparin in plasma samples causes nonspecific binding to histones on Western blots. J Immunol Methods 226(1–2): 11–18. doi: 10.1016/s0022-1759(99)00043-5
[18]
Zhao D, Ding R, Mao Y, Wang L, Zhang Z, et al. (2012) Heparin rescues sepsis-associated acute lung injury and lethality through the suppression of inflammatory responses. Inflammation 35(6): 1825–1832. doi: 10.1007/s10753-012-9503-0
[19]
Cox CS, Zwischenberger JB, Traber DL, Traber LD, Haque AK, et al. (1993) Heparin improves oxygenation and minimizes barotrauma after severe smoke inhalation in an ovine model. Surg Gynecol Obstet 176(4): 339–349.
[20]
Murakami K, Enkhbaatar P, Shimoda K, Mizutani A, Cox RA, et al. (2003) High-dose heparin fails to improve acute lung injury following smoke inhalation in sheep. Clin Sci(Lond) 104(4): 349–356. doi: 10.1042/cs20020258
[21]
Monestier M, Fasy TM, Losman MJ, Novick KE, Muller S (1993) Structure and binding properties of monoclonal antibodies to core histones from autoimmune mice. Mol Immunol 30(12): 1069–1075. doi: 10.1016/0161-5890(93)90153-3
[22]
Matute-Bello G, Frevert CW, Martin TR (2008) Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 295(3): L379–L399. doi: 10.1152/ajplung.00010.2008
[23]
Su X, Bai C, Hong Q, Zhu D, He L, et al. (2003) Effect of continuous hemofiltration on hemodynamics, lung inflammation and pulmonary edema in a canine model of acute lung injury. Intensive Care Med 29(11): 2034–2042. doi: 10.1007/s00134-003-2017-3
[24]
Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6): 805–820. doi: 10.1016/j.cell.2010.01.022
[25]
Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, et al. (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464(7285): 104–107. doi: 10.1038/nature08780
[26]
Raoof M, Zhang Q, Itagaki K, Hauser CJ (2010) Mitochondrial peptides are potent immune activators that activate human neutrophils via FPR-1. J Trauma 68(6): 1328–1332. doi: 10.1097/ta.0b013e3181dcd28d
[27]
Hirsch JG (1958) Bactericidal action of histone. J Exp Med 108(6): 925–944. doi: 10.1084/jem.108.6.925
[28]
Brinkmann V, Laube B, Abu Abed U, Fauler B, Uhlemann Y, et al. (2004) Neutrophil extracellular traps kill bacteria. Science 303(5663): 1532–1535. doi: 10.1126/science.1092385
[29]
Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389(6648): 251–260. doi: 10.1038/38444
[30]
Furnrohr BG, Groer GJ, Sehnert B, Herrmann M, Voll RE (2007) Interaction of histones with phospholipids–implications for the exposure of histones on apoptotic cells. Autoimmunity 40(4): 322–326. doi: 10.1080/08916930701356457
[31]
Freeman CG, Parish CR, Knox KJ, Blackmore JL, Lobov SA, et al. (2013) The accumulation of circulating histones on heparan sulphate in the capillary glycocalyx of the lungs. Biomaterials 34(22): 5670–5676. doi: 10.1016/j.biomaterials.2013.03.091
[32]
Ganapathy V, Shyamala CS (2005) Effect of histone H1 on the cytosolic calcium levels in human breast cancer MCF 7 cells. Life Sci 76(22): 2631–2641. doi: 10.1016/j.lfs.2005.01.002
[33]
Gamberucci A, Fulceri R, Marcolongo P, Pralong WF, Benedetti A (1998) Histones and basic polypeptides activate Ca2+/cation influx in various cell types. Biochem J 331 (Pt 2): 623–630.
[34]
Kleine TJ, Lewis PN, Lewis SA (1997) Histone-induced damage of a mammalian epithelium: the role of protein and membrane structure. Am J Physiol 273 (6 Pt 1): C1925–C1936.
[35]
Caudrillier A, Kessenbrock K, Gilliss BM, Nguyen JX, Marques MB, et al. (2012) Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest 122(7): 2661–2671. doi: 10.1172/jci61303
[36]
Pal PK, Starr T, Gertler MM (1983) Neutralization of heparin by histone and its subfractions. Thromb Res 31(1): 69–79. doi: 10.1016/0049-3848(83)90008-7
[37]
Fuchs TA, Bhandari AA, Wagner DD (2011) Histones induce rapid and profound thrombocytopenia in mice. Blood 118(13): 3708–3714. doi: 10.1182/blood-2011-01-332676
[38]
Hayashi T, Kumagai K, Naito S, Goto K, Kaseno K, et al. (2012) Preprocedural therapeutic international normalized ratio influence on bleeding complications in atrial fibrillation ablation with continued anticoagulation with warfarin. Circ J 77(2): 338–344. doi: 10.1253/circj.cj-12-0743
[39]
Warren BL, Eid A, Singer P, Pillay SS, Carl P, et al. (2001) Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286(15): 1869–1878. doi: 10.1001/jama.286.15.1869
[40]
Casu B, Naggi A, Torri G (2010) Heparin-derived heparan sulfate mimics that modulate inflammation and cancer. Matrix Biol 29(6): 442–452. doi: 10.1016/j.matbio.2010.04.003
[41]
Barzu T, Van Rijn JL, Petitou M, Molho P, Tobelem G, et al. (1986) Endothelial binding sites for heparin: specificity and role in heparin neutralization. Biochem J 238(3): 847–854. doi: 10.1016/0049-3848(86)91575-6
[42]
Weinbaum S, Tarbell JM, Damiano ER (2007) The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 9: 121–167. doi: 10.1146/annurev.bioeng.9.060906.151959
[43]
Schmidt EP, Yang Y, Janssen WJ, Gandjeva A, Perez MJ, et al. (2012) The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 18(8): 1217–1223. doi: 10.1038/nm.2843
